Abstract

The metallic everolimus drug-eluting stents (DES) and polymeric everolimus bioresorbable vascular scaffolds (BVS) are coated with the same antiproliferative drug. It is uncertain if, during the bioresorption process, the neointimal response of everolimus BVS differs from that of everolimus DES. A total of 31 lesions treated with a single everolimus BVS, and 19 lesions treated with everolimus DES and imaged with optical coherence tomography at 1 year, were investigated. Neointimal response was assessed as a percentage of uncovered struts, neointimal thickness, in-stent/scaffold area obstruction, and pattern of neointima. Both scaffolds presented with similar neointimal response. However, the everolimus BVS presented with a trend toward higher proportion of intraluminal masses than everolimus DES did.

Background DES decrease the risk of restenosis by reducing the neointimal response. However, DES may impair strut coverage, and this has been associated with late stent/scaffold thrombosis. BVS may overcome the risk of stent/scaffold thrombosis when completely resorbed. It is unknown if, during the bioresorption process, the neointimal response of the everolimus BVS (Absorb, Abbott Vascular, Santa Clara, California) differs from that of the metallic everolimus DES (Xience, Abbott Vascular).

Methods A total of 19 lesions were treated with a single everolimus DES, and 31 lesions were treated with everolimus BVS and imaged with optical coherence tomography at 1 year. Neointimal response was assessed as percentage of uncovered struts, neointimal thickness, in-stent/scaffold area obstruction, and pattern of neointima.

Conclusions The everolimus BVS (Absorb) demonstrated a similar neointimal response as the everolimus DES (Xience). However, the presence of intraluminal masses at 12 months in a small proportion of patients warranted watchful follow-up of these cases.

Compared to bare-metal stents, drug-eluting stents (DES) have dramatically decreased the neointimal response and need for target lesion revascularization at mid- and long-term follow-up (1). However, the neointimal response observed with DES has been characterized by a higher incidence of uncovered struts (2). Lack of tissue coverage has been shown to trigger platelet activation around the uncovered struts and has been implicated as one of the most important risk factors associated with stent/scaffold thrombosis (ST) (3,4). Prolongation of dual antiplatelet therapy is aimed at protecting against ST; however, the optimal duration of therapy has yet to be fully clarified (5,6).

Bioresorbable vascular scaffolds (BVS) may potentially overcome the risk of ST and need for lifelong treatment with dual antiplatelet therapy. At 2-year follow-up, the everolimus BVS (Absorb, Abbott Vascular, Santa Clara, California) has disappeared and has been replaced by connective proteoglycans and occasional smooth muscle cells (7). Consequently, no foreign body remains and vessel vasomotion and vessel wall remodeling may potentially be restored (8). However, during the bioresorption process, the long chains of the polymer are hydrolyzed into small chains and phagocytosed by macrophages. The resulting lactide molecules are metabolized to carbon dioxide and water in the Krebs cycle. This process substantially differs from the neointimal response observed with metallic DES coated with a nonerodible polymer (3). During the bioresorption process, it is at present uncertain if the polymeric everolimus BVS may potentially precipitate a different neointimal response compared with metallic everolimus DES that contains the same amount of antiproliferative drug with a similar release time.

Optical coherence tomography (OCT) is an intravascular imaging technique with high axial resolution (10 to 15 μm). Assessment of the neointimal response using OCT in vivo, when compared with histology, has previously been demonstrated to have an excellent ability to discern the subtle differences in neointimal coverage above metallic struts (9). Moreover, intraluminal masses suggestive of thrombus have been shown to be related to the presence of uncovered struts as assessed by OCT (10,11).

The aim of the present study is to compare the neointimal response of the metallic everolimus DES (Xience, Abbott Vascular, Santa Clara, California) with the everolimus BVS (Absorb) using identical OCT methodologies.

Methods

Population

The present study is a post hoc analysis of the RESOLUTE All Comers and the ABSORB (A Bioabsorbable Everolimus-Eluting Coronary Stent System for Patients With Single De Novo Coronary Artery Lesions) trials. The inclusion criteria and study design of both trials have previously been published (12,13). In brief, the RESOLUTE trial is a multicenter, randomized trial comparing the RESOLUTE zotarolimus DES with the Xience everolimus DES. The RESOLUTE trial is an all-comers trial that included all patients presenting with ST-segment elevation myocardial infarction and patients with all types of complex lesions suitable for treatment with a 2.25- to 4.00-mm diameter device. Overlap stenting was allowed. A randomized subset of patients underwent angiographic follow-up at 13 months. OCT was performed at 13 months as an optional investigation in selected sites where OCT was available (13,14).

The ABSORB Cohort B trial is a multicenter, single-arm trial that included 101 patients that presented with stable, silent angina and noncomplex coronary lesions suitable for treatment with a single 3.0 × 18-mm everolimus-eluting BVS (Absorb). The study design divided the global population in 2 separate groups: Cohort B1 (n = 45) with angiographic follow-up at 6 months and Cohort B2 (n = 56) with angiographic follow-up at 12 months. Patients with ostial, bifurcation, or chronic total occlusion lesions or with acute myocardial infarction within the 3 days preceding the index procedure were excluded per protocol. OCT was an optional investigation performed in selected centers in which OCT was available at follow-up. The clinical, angiographic, and OCT results of the Cohort B1 at 6-month follow-up have been already reported (12).

The present study selected all patients and lesions treated with a single Xience stent or Absorb scaffold, who were imaged with OCT at 12 to 13 months, and were included in the RESOLUTE or ABSORB Cohort B2 trials. To allow a comparison of a similar patients and similar lesions, all patients with ostial, bifurcation, or chronic total occlusion lesions or who presented with ST-segment elevation myocardial infarction (in the RESOLUTE All-Comers trial) were excluded. Patients with overlapped stents were also excluded.

Study device and procedure

The Xience V is a balloon expandable stent composed of a cobalt-chromium alloy platform coated with a nonerodible biocompatible polymer. The coating is composed of an acrylic base and a fluorinated polymer that contains and releases 100 μg/cm2 of the antiproliferative drug everolimus (Novartis, Basel, Switzerland). Approximately 80% of the drug is released within 30 days after implantation, with nearly all the drug released within 4 months (1). Everolimus is a cellular, cytostatic antiproliferative drug that inhibits the mammalian target of rapamycin pathway. The inhibition of the mammalian target of rapamycin pathway results in a reduced proliferation and migration of smooth muscle cells and, therefore, reduces the formation of neointimal tissue. The strut thickness of the metallic platform is 81 μm and the thickness of the nonerodible polymer/drug is approximately 5 to 6 μm (1).

Absorb is a balloon expandable, fully resorbable device. The scaffold is constructed of poly-L lactide and is coated with a bioresorbable poly-D, L lactide coating that contains and controls the release of everolimus. The dose and release rate of everolimus are identical to those of Xience. Based on studies in a porcine model, the polymeric struts are resorbed approximately 2 years after implantation (7). The total strut thickness of the BVS polymeric strut at the time of implantation is 156 μm.

Device implantation was performed according to standard procedural techniques and anticoagulation regimens. Direct stenting was permitted in the RESOLUTE trial, whereas in the ABSORB trial, all lesions underwent mandatory pre-dilation. Post-dilation and bailout stenting was allowed at the operator's discretion in both trials. All patients received at least 75 mg of acetylsalicylic acid and a loading dose of 300 to 600 mg of clopidogrel before the procedure. Dual antiplatelet therapy was recommended for a minimum period of 6 months.

Quantitative coronary angiography analysis

Quantitative coronary angiography was analyzed by an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) using the CAAS II analysis system (Pie Medical BV, Maastricht, the Netherlands). In each lesion, the treated and peritreated regions (defined as 5 mm proximal and distal to the device edges) were analyzed at baseline and at 1-year follow-up. The following QCA parameters were measured: the interpolated-reference vessel diameter, the minimal luminal diameter (MLD), and the percentage diameter stenosis. Late luminal loss was estimated as the difference between the MLD at post-implantation and at follow-up using matched angiographic views.

OCT acquisition

OCT imaging was performed using 3 different OCT systems: the M2 and M3 Time-Domain Systems and the C7XR Fourier-Domain System (LightLab Imaging, Westford, Massachusetts). The M2 acquisitions were performed with the occlusive technique, and with the M3 and C7 OCT systems, images were acquired with nonocclusive techniques. All recordings were performed using the recommended standard procedure for each type of OCT system (15).

OCT analysis

Metallic stents (such as Xience) and bioresorbable scaffolds (such as Absorb) have differing imaging properties when analyzed by OCT. The different physical properties of metallic and polymeric structures cause dissimilar reflection of the OCT light beam. With metallic struts, the light beam is completely reflected by the struts, resulting in a bright hyperintense signal in front of the struts with a shadow behind. Conversely, the polymeric scaffolds are transparent to the light beam allowing the visualization of the vessel wall located behind the struts without shadowing behind (16). The polymeric struts are rendered as hyperintense frames surrounding hyporeflective core areas (black boxes). However, the hyperintense frame has the same intensity as the neointimal tissue, hampering the assessment of the strut contour when covered by neointima. Figure 1 shows a representative OCT image of metallic and polymeric struts.

OCT analysis of the RESOLUTE and ABSORB trials was undertaken by an independent core laboratory (Cardialysis) using the proprietary software for offline analysis (LightLab Imaging). After adjusting for pullback speed, the analysis of contiguous cross sections was performed at 1-mm longitudinal intervals within the treated segment and for 5 mm proximal and distal to the stent/scaffold edges. Lumen area was automatically drawn and minor corrections made whenever necessary. With metallic devices, the stent area was drawn at the endoluminal site of the hyperintense signal of the metallic struts. However, in case of polymeric poly-lactide structures, the OCT protocol analysis of the ABSORB trial guided the analysts to draw the scaffold area at the abluminal border of the black boxes to allow assessment of the neointima above and between the struts. To allow comparison of the 2 different devices, an independent analyst selected the endoluminal border of the black box to delineate the scaffold area. The neointimal area was estimated as scaffold area—lumen area and exclusively represents the neointima above the struts. The neointimal area was normalized per stent/scaffold size as “in-stent/scaffold area obstruction” and estimated as: [neointimal area/scaffold area] × 100. Qualitative assessment of the pattern of coverage (homogeneous vs. heterogeneous) was assessed, as previously reported, at the site of the maximal in-stent/scaffold area obstruction in each lesion (12,17). Reference vessel area was estimated as: [maximal lumen diameter at the proximal edge + maximal lumen diameter at the distal edge]/2. Area stenosis was estimated as: 100 – [(minimal lumen diameter/reference vessel area) × 100].

With metallic stents, the neointimal thickness (NIT) was automatically measured from the endoluminal side of the strut hyperintense signal to the lumen contour following the center of gravity of the vessel. Because the strut thickness of the Xience is around 90 μm and the axial resolution of the OCT is around 10 μm, nonapposed struts were defined whenever the distance (endoluminal strut leading edge – lumen) was higher than 100 μm. With polymeric scaffolds, NIT was drawn from the endoluminal border of the black box to the lumen contour. Because the mean ± SD thickness of the endoluminal frame post-implantation (without tissue coverage) is 34 ± 6 μm; uncovered struts at follow-up were defined when the NIT was ≤30 μm. Nonapposed struts were defined when the abluminal border of the hyperintense frame was separated from the vessel wall. At follow-up, protruding masses attached to the vessel wall or floating masses without contact with the vessel wall have been associated with the presence of thrombi (11). However, the distinction between thrombi and neointimal protrusions into the lumen is not possible. Therefore, any irregular mass attached to the struts or floating into the lumen has been classified as intraluminal mass without distinction between thrombus and neointima (18).

Statistical analysis

Statistical analysis was performed with the SPSS software, version 15.0 (SPSS Inc., Chicago, Illinois). Discrete variables are presented as counts and percentages, and continuous variables as means ± SD when normally distributed and median (interquartile range (IQR)) when non-normally distributed. Percentages of discrete variables at lesion and cross-sectional level refer to the number of lesions or cross sections with at least 1 nonapposed, uncovered or nonapposed plus uncovered strut according to the total amount of observations. Comparisons of continuous variables were estimated using the nonparametric Mann-Whitney U test and comparisons of discrete variables were estimated with the chi-square test. Adjustments for clustering data at lesion, cross section, or strut level analysis were not performed. A 2-sided p value ≤0.05 was considered statistically significant.

Results

Baseline clinical characteristics

A total of 50 lesions (19 treated with everolimus DES and 31 treated with everolimus BVS) in 44 patients (14 vs. 30, respectively) were selected for the present study. Baseline clinical characteristics are shown in Table 1. Demographics and cardiovascular risk factors were similar in both groups except for a history of prior myocardial infarction (57.1% in the everolimus DES group vs. 10.0% in the everolimus BVS group; p < 0.01). The presence of diabetes mellitus tended to be more frequent with the everolimus DES group than with the everolimus BVS group (21.4% vs. 6.7%; p = 0.15). The everolimus DES group also tended to present with more acute coronary syndromes as the clinical indication at the index procedure than did the everolimus BVS group (35.7% vs. 20.0%; p = 0.26) and had a larger number of diseased vessels (50.0% vs. 90.0% single-vessel disease; p = 0.01).

Procedural and quantitative angiographic characteristics

Procedural and angiographic characteristics are shown in Table 2. At pre-implantation, the everolimus DES group presented with longer lesions than the everolimus BVS group did (lesion length 13.2 ± 5.9 mm vs. 9.9 ± 3.0 mm; p = 0.03). The interpolated reference vessel diameter, MLD, and diameter stenosis were similar in both groups. The most frequently treated vessel was the left anterior descending artery (52.6% vs. 61.3%; p = 0.10). Lesion type was more complex with the everolimus DES than with the everolimus BVS (42.1% vs. 6.5% of lesions were classified as type C; p < 0.01). At post-implantation, both devices presented similar MLD and diameter stenosis. At 1-year follow-up, the lumen loss was similar in both devices (0.21 mm [IQR: 0.08 to 0.31 mm] vs. 0.24 mm [IQR: 0.04 to 0.42 mm]; p = 0.42).

The everolimus DES presented with a higher percentage of lesions with nonapposed struts than the everolimus BVS did (57.9% vs. 25.8%; p = 0.02), although the percentage of nonapposed struts was smaller with the everolimus DES than with the everolimus BVS (1.1% vs. 2.2%; p<0.01) at strut level analysis. The percentage of uncovered struts was similar between the everolimus DES and the everolimus BVS at lesion level, cross-section level, and strut level. Nonapposed plus noncovered struts were more frequently found with the everolimus DES than with the everolimus BVS at the 3 level analyses.

There was a nonstatistically significant trend to a higher rate of heterogeneous pattern of tissue coverage with the everolimus DES than with the everolimus BVS (21.1% vs. 6.5%; p = 0.12). Intraluminal masses were rarely observed at 1 year in the overall study population. However, the everolimus BVS presented with a higher percentage of lesions with intraluminal masses at lesion level (0% for the everolimus DES vs. 12.9% for the everolimus BVS; p = 0.10) and at cross-section level analysis (0% vs. 4.2%; p < 0.01).

Discussion

The main results of our study are: 1) at 1-year follow-up, the amount and distribution of the neointimal tissue was similar with both everolimus DES and everolimus BVS as assessed by OCT; 2) the percentage of uncovered struts was also similar with both groups; 3) the everolimus DES group tended to present with a higher percentage of heterogeneous neointimal tissue than the everolimus BVS group did; 4) intraluminal masses were rarely observed at 1 year, however, there was a trend toward a higher percentage of intraluminal masses with the everolimus BVS than with the everolimus DES.

The present study is the first OCT report comparing the neointimal response of the fully resorbable polymeric everolimus BVS (Absorb) with the nonerodible metallic everolimus DES (Xience). Both devices contain and release the same amount of drug over the same time. In pre-clinical porcine models using the previous generation of Absorb (1.0), the molecular weight loss of the polymer implanted in coronary arteries was 70% as assessed by gel permeation chromatography at 1 year (7). It would be of significant concern if the bioresorption of the polymer led to a higher inflammatory response when compared with standard DES. The amount of polymer and its speed of degradation into oligomers or monomers have previously been correlated with the intensity of the inflammatory reaction due to the activation of phagocytes (19). It is noteworthy that between 4% and 15% of the polymeric struts presented with foreign body reactions (in the form of granulomas) and giant cells (respectively) in a swine model at 6-month follow-up (7). However, the inflammatory reaction observed with the everolimus BVS at 6 months was shown to be similar to other DES (20), and moreover, the inflammatory reaction decreased over time, being practically 0 at 2 years post-implantation in the same pre-clinical model (7). Although OCT has limited ability to assess vessel inflammation, our study is in accordance with the pre-clinical studies. There were no differences in the amount of neointima and type of neointimal tissue (heterogeneous vs. homogeneous) between everolimus DES and everolimus BVS.

The percentage of uncovered struts (5.3% with the everolimus DES vs. 4.5% with the everolimus BVS) and the amount of NIT (121 μm vs. 136 μm) demonstrated in the present study is similar to other DES. Sirolimus DES demonstrated 5.7% to 12.3% of uncovered struts (11,21) and 70 to 120 μm of NIT at 1-year follow-up (21,22). Paclitaxel DES have been shown to have similar rates of uncovered struts (4.9%) and NIT (181 μm) at 9-month follow-up (23,24). Although it is commonly accepted that the incidence of uncovered struts is a major determinant of stent/scaffold thrombosis (ST) based on postmortem histological studies (4), these results must be read carefully due to the small sample size it is derived. Figure 3 shows 2 examples of uncovered struts.

Intraluminal masses have been associated with thrombus (11). Intraluminal masses were more frequently observed with everolimus BVS (in 4.2% of cross sections and in 12.9% of lesions) compared with everolimus DES (in 0 cross sections/lesions). It is uncertain if the polymeric material has a different thrombogenicity than other metallic DES. Sirolimus DES and paclitaxel DES presented with similar rates of visible intraluminal masses suggestive of thrombus (28% and 11% of lesions) as everolimus BVS at a median follow-up of 11 months (10). In keeping with a previous publication (25), we observed intraluminal masses only in lesions with uncovered struts. It has been previously demonstrated that optimal deployment of the BVS at the time of the index procedure, with a low risk of nonapposed struts and no evidence of scaffold fracture, can potentially decrease the amount of uncovered struts and thrombi at 6-month follow-up (25). For these reasons, quantitative coronary angiography or intravascular imaging techniques performed before BVS implantation may be of major interest to assess the vessel size and to guide an appropriate balloon/artery ratio. Moreover, to decrease the risk of ST, it seems reasonable that patients receiving an everolimus BVS should be treated with dual antiplatelet therapy according to the current guidelines for metallic DES (26). Further investigations, with larger numbers of patients and longer term follow-up, are required to substantiate the findings of this study.

Study limitations

The first limitation of the present study is the low number of patients/lesions and the nonrandomized nature of our study. The RESOLUTE trial was an all-comers trial that included an all-comer population, whereas the ABSORB trial was a phase I study that included a selected population. Although we have tried to compare similar groups of patients, a bias of patient and lesion characteristics may still be present due to the differences in the inclusion criteria used in each trial. However, the difference in stent/scaffold size between groups does not invalidate the results because it is well established that the neointimal response is not related to the vessel or stent size (27,28). Second, because metallic stents do not allow the assessment of the abluminal border of metallic struts, the differences in neointimal tissue are limited to the neointima located above the struts. Of note, polymeric struts allow the assessment of neointimal tissue above and between struts. However, to compare both devices with a similar approach, we have measured the neointimal tissue located above the polymeric struts. Therefore, the OCT methodology used in the present study differs from that used in other studies with BVS. Finally, there was a lack of randomization or consecutive OCT acquisitions of the patients included in the present study. In both trials, OCT was performed as an optional investigation in selected centers at follow-up. However, for the patients with scheduled angiography at follow-up, there was excellent compliance of angiographic control (80% and 98% with the RESOLUTE and ABSORB trials, respectively).

Conclusions

The polymeric everolimus BVS (Absorb) demonstrated a similar neointimal response as the metallic everolimus DES (Xience). However, the presence of intraluminal masses at 12 months in a small proportion of patients treated with bioresorbable scaffolds warranted watchful follow-up of these cases.

Acknowledgments

The authors would like to thank the Biomedical Research Institute of Bellvitge (IDIBELL, Spain) for the grant awarded to the first author.

Footnotes

Dr. Windecker received research grants to the institution from Abbott, Biotronik, Biosensors, Boston Scientific, Cordis, and Medtronic. Prof. Dudek has received research grants or served as consultant/advisory board member for Abbott, Adamed, AstraZeneca, Biotronik, Balton, Bayer, BBraun, BioMatrix, Boston Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, GlaxoSmithKline, Invatec, Medtronic, The Medicines Company, Merck & Co. and Schering-Plough, Nycomed, Orbus-Neich, Pfizer, Possis, Promed, Sanofi-Aventis, Siemens, Solvay, Terumo, and Tyco. Dr. Smits received travel and speaking fees from Abbott Vascular and is a consultant for Blue Medical. Dr. Chevalier is a consultant for Abbott Vascular. Drs. Rapoza and Ms. Veldhof are full-time employees with Abbott Vascular. Dr. Ormiston is on the advisory board for and received minor honoraria from Abbott Vascular and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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